NaOH-Mediated Direct Synthesis of Quinoxalines from o-Nitroanilines and Alcohols via a Hydrogen-Transfer Strategy

Article abstract of DOI:10.1021/acs.joc.0c02453

A NaOH-mediated sustainable synthesis of functionalized quinoxalines is disclosed via redox condensation of o-nitroamines with diols and α-hydroxy ketones. Under optimized conditions, various o-nitroamines and alcohols are well tolerated to generate the desired products in 44-99% yields without transition metals and external redox additives.

Full text of DOI:10.1021/acs.joc.0c02453

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Article
NaOH-Mediated Direct Synthesis of Quinoxalines from
o‑Nitroanilines and Alcohols via a Hydrogen-Transfer Strategy
Yan-Bing Wang, Linlin Shi, Xiaojie Zhang, Lian-Rong Fu, Weinan Hu, Wenjing Zhang, Xinju Zhu,*
Xin-Qi Hao, and Mao-Ping Song*
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ABSTRACT: A NaOH-mediated sustainable synthesis of function-
alized quinoxalines is disclosed via redox condensation of o-
nitroamines with diols and α-hydroxy ketones. Under optimized
conditions, various o-nitroamines and alcohols are well tolerated to
generate the desired products in 44−99% yields without transition
metals and external redox additives.
Scheme 1. Strategies for Syntheses of Quinoxalines
INTRODUCTION
■
As an important class of nitrogen heterocycles, quinoxalines are
recognized as valuable synthetic targets because of their wide
existence in medicinally important and biologically active
compounds.1 Meanwhile, quinoxaline chromophores have
demonstrated diverse applications in materials science for the
development of novel organic optoelectronics.2 Consequently,
considerable efforts have been made to access substituted
quinoxaline scaffolds.3 The conventional preparation of
quinoxalines usually involves the annulation of o-diaminoben-
zenes with ketone derivatives, alkene, alkyne, and other
reagents.4 In addition, transition-metal-catalyzed oxidative
cyclization of N-arylenamines with azides, nitromethane, and
nitrites has been developed.5 Recently, quinoxalines could also
be prepared utilizing o-diisocyanoarenes as radical acceptors via
a radical cascade cyclization strategy.6 Despite the above
progress, the development of efficient and environmentally
friendly methods using simple and readily available starting
materials is still desired.
The past few decades have witnessed the thriving develop-
ment of acceptorless dehydrogenation coupling (ADC) and
hydrogen-transfer (HT) strategy, which plays an important role
in the construction of C−C bonds,7 C−N bonds,8 and
heterocycles.9 Meanwhile, biomass-derived alcohols are widely
utilized as coupling partners as they are inexpensive, green, and
readily available with great structural diversity. In this context,
the dehydrogenative condensation between aromatic amines
and diols was reported using Ir, Ru, Mn, and Co complexes,
which represents an efficient and sustainable synthetic route to
access quinoxalines (Scheme 1a).10 Compared with aromatic
diamines, nitroarenes are more stable functionalized materials,
which could react with other reducing components to form
various nitrogen-containing heterocycles.11 Recently, Zhang,
Kundu, and Nguyen groups have independently reported the
syntheses of quinoxalines via transfer hydrogenation between o-
nitroanilines and vicinal diols catalyzed by Ru, Ir, Co, Fe, and Ni
transition metals (Scheme 1b).10c,f,12 Nevertheless, most of the
above protocols employ transition-metal catalysts, special
ligands, or external additives, which make them difficult to be
applied in industrial manufacturing.
Received: October 15, 2020
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To overcome the above limitations, base-mediated C−C and
C−N coupling13 have been disclosed to realize α-alkylation of
ketones,14 β-alkylation of alcohols,15 N-alkylation of amines,16
and other transformation.17 On the basis of the above literature
and our experience in ADC and HT reactions,18 we herein
reported a NaOH-mediated one-pot synthesis of substituted
quinoxalines through redox condensation of o-nitroanilines and
vicinal diols or α-hydroxy ketones (Scheme 1c). In this synthetic
protocol, alcohol and the nitro group serve as the hydrogen
donor and hydrogen acceptor, respectively, generating water as
the only byproduct. Meanwhile, excess alcohols are required
because each alcohol function provides only two electrons, while
the reduction of a nitro group requires six electrons.12c
substantially decreased yield was observed when performing the
reaction under air (entry 12, Table 1). As the base-promoted
oxidation of alcohols to carbonyl compounds under an inert
atmosphere is also well-developed via a transfer dehydrogen-
ation process (MPV-O mechanism),13,14,16c,17b,19 the inter-
vention of oxygen as an oxidizing agent might not be involved in
the current redox condensation process as o-nitroanilines serve
both as the hydride acceptor and reactant. When the dosage of
NaOH was decreased to 0.3 equiv, product 3a was obtained in
37% yield, which implies that the dosage of NaOH plays an
important role in determining the reaction efficiency (entry 13,
Table 1).20 No product was isolated in the absence of NaOH,
indicating the necessity of base (entry 14, Table 1). Finally, a
control experiment using new glassware and 4 N grade NaOH
was conducted, which also gave product 3a in 91% yield (entry
15, Table 1). Meanwhile, inductively coupled plasma-atomic
emission spectrometry (ICP-AES) measurements of AR grade
NaOH were also performed to check the transition-metal
residues. The contents of Cr, Mn, Fe, Co, Ni, Cu, Zn, Ru, Rh, Pd,
Ir, and Pt were found to be less than the detection limit (0.1
ppm), indicating that the redox condensation between o-
nitroanilines and alcohols is promoted by NaOH itself rather
than trace-metal impurities.
RESULTS AND DISCUSSION
■
We commenced our study by investigating the model reaction of
o-nitroaniline (1a) and 2,3-butandiol (2a) under various
reaction conditions (Table 1). To our delight, quinoxaline 3a
a
Table 1. Optimization of Reaction Conditions
With the optimized conditions in hand, the redox
condensation between various o-nitroanilines and 2,3-butandiol
was investigated (Table 2). To our delight, a series of mono-
substituted o-nitroanilines bearing OMe, Me, F, Cl, and Br
groups at different positions were well tolerated to afford
quinoxaline 3a−h in 61−98% yield. For 3-methyl-2-nitroaniline
and 6-methyl-2-nitroaniline substrates, the same product 3b
could be obtained in an almost identical yield. However, product
3e was isolated in much higher yield (98%) starting from 5-
chloro-2-nitroaniline. In general, o-nitroanilines bearing elec-
tron-donating groups at the C4 position provided the
corresponding product (3c) in higher yields than those of
electron-deficient o-nitroanilines (3d−f), which might be
ascribed to the enhanced nucleophilicity of the amino group.
On the contrary, C5-substituted electron-rich o-nitroanilines
provided quinoxalines (3g and 3h) in lower yields than the
electron-deficient one (3e), which could arise from the
decreased reducibility of the nitro group. Next, di-substituted
o-nitroanilines could also react with 2a to deliver products 3i−k
in 63−94% yields.
Encouraged by the above results, the generality and
limitations of current protocol were further evaluated through
variation of diols (Table 3). Initially, symmetrical aryl- and alkyl-
substituted vicinal diols were examined, which gave quinoxalines
4a−f in 52−98% yields. Next, a series of unsymmetrical diols
were employed, which required a higher temperature and longer
reaction time to provide quinoxalines 4g−p in 48−82% yields.
For vicinal diols attached with aryl groups, installation of an
electron-rich substituent OMe (4e) at the phenyl ring was
beneficial, which is probably due to the increased oxidizability of
the hydroxyl to carbonyl group. For alkyl-substituted diols, the
alkyl chain length has a great influence on reactivity with product
4o obtained in 82% yield. Finally, the reaction between
substituted o-nitroanilines and vicinal diols was explored to
furnish products 4q−z in 46−98% yield. Notably, when 4 N
grade NaOH was utilized, the corresponding products 4a, 4f,
and 4g were also obtained in comparable yields.
entry
base
KOtBu
NaOtBu
KOH
NaOH
CsOH·H2O
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
solvent
temp (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
o-xylene
dioxane
tAmOH
neat
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
100
120
150
120
120
120
120
12
12
12
12
12
12
12
12
12
3
71
74
49
90
40
74
33
48
76
92
90
24
37
0
9
10
11
1
3
3
3
b
12
13
c
14
15
d
NaOH
3
92
a
Reaction conditions: 1a (0.5 mmol), 2a (2.0 mmol), base (0.5 equiv,
AR grade, 96% purity), solvent (1.0 mL), under Ar. Isolated yields.
Under air. NaOH (0.3 equiv). Virgin glassware and 4 N grade
b
c
d
t
NaOH (99.99% purity) were used. AmOH: 2-methyl-2-butanol.
was isolated in 71% yield in the presence of KOtBu (0.5 equiv) in
toluene (1 mL) at 100 °C for 12 h under Ar (entry 1, Table 1).
The utilization of NaOtBu gave 3a in 74% yield with slightly
higher efficiency (entry 1, Table 1). Subsequently, other strong
bases, such as KOH, NaOH, and CsOH·H2O, were also
evaluated, indicating that NaOH (of AR grade and 96% purity
was used unless otherwise noted) was the best choice to provide
product 3a in 90% yield (entry 3−5, Table 1). Next, various
solvents, such as o-xylene, dioxane, and tAmOH, were examined,
which all gave 3a in decreased yield (entry 6−8, Table 1).
Interestingly, quinoxaline 3a could also be isolated in 76% yield
without any solvent (entry 9, Table 1). To improve the reaction
efficiency, the effects of reaction temperature and time were
studied. It was found that the desired product 3a could be
isolated in 92% yield at 120 °C for 3 h (entry 10, Table 1). When
the reaction was carried out at 150 °C for 1 h, similar results
could also be obtained (entry 11, Table 1). Furthermore, a
In addition, various α-hydroxy ketones were also found to be
suitable substrates to afford the desired product 4 in 44−99%
yield (Table 4). Especially, when electron-rich groups such as
B
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a
Table 2. Substrate Scope of o-Nitroanilines
a
Reaction conditions: 1 (0.5 mmol), 2a (2.0 mmol), NaOH (0.5 equiv, AR grade, 96% purity), toluene (1.0 mL), under Ar. Isolated yields.
a
Table 3. Substrate Scope of o-Nitroanilines and Vicinal Diols
a
Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), NaOH (0.5 equiv, AR grade, 96% purity), toluene (1.0 mL), 120 °C, 3 h, under Ar. Isolated
b
c
d
yields. 1 (0.1 mmol), 2 (0.4 mmol). 150 °C, 12 h. 4 N grade NaOH (99.99% purity).
methoxyphenyl and furyl were introduced, quinoxalines 4ab−ai
could be obtained in 75−99% yields. Notably, when 4 N grade
NaOH was utilized, the corresponding products 4aa and 4ab
were also obtained in comparable yields.
C
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a
Table 4. Substrate Scope of o-Nitroanilines and α-Hydroxy Ketones
a
Reaction conditions: 1 (0.1 mmol), 5 (0.4 mmol), NaOH (0.5 equiv, AR grade, 96% purity), toluene (1.0 mL), 120 °C, 3 h, under Ar. Isolated
b
c
yields. 150 °C, 12 h. 4 N grade NaOH (99.99% purity).
a
Table 5. Substrate Scope of 1,2-Dinitrobenzene and Vicinal Diols
a
Reaction conditions: 1,2-dinitrobenzene (0.5 mmol), vicinal (2.0 mmol), NaOH (3.0 equiv, AR grade, 96% purity), toluene (1.0 mL), 150 °C, 12
h, under Ar. Isolated yields.
Notably, 1,2-dinitrobenzene also proved to be a promising
substrate, which reacted with various vicinal diols to afford the
desired product 3a, 4a, 4f, and 4aa in 41−52% yield when the
reaction was performed at higher temperatures (Table 5).
Compared with o-nitroanilines, the lack of intramolecular N−
H···O interaction and the reduction of two nitro groups could be
the reason that requires excess NaOH (3 equiv) to fulfill the
transformation.
To demonstrate the synthetic utility of the current strategy, a
gram-scale production was performed to give quinoxaline 3a in
87% yield (Scheme 2). Furthermore, the obtained product 3a
could undergo oxidation, reduction, and transfer hydrogenation
to give products 7, 8, and 9 in 67, 88, and 96% yields,
respectively.
other strong bases, such as NaOMe (31%), NaH (42%),
NaOtBu (71%), and KOtBu (74%), also generated product 3a in
moderate to good yields, while other weak bases led to decreased
or no reaction efficiency (such as Na2CO3, 0%).13,16c,20b To
explore the reaction mechanism, a set of control experiments
were conducted (Scheme 3). First, quinoxaline 3a could be
obtained in 86% yield in the presence of both KOH (0.5 equiv)
and Na2CO3 (0.25 equiv) (Scheme 3a), indicating that the
existence of both Na+ and OH− is necessary. On the contrary,
the combination of NaOH (0.5 equiv) and 15-crown-5 did not
led to detectable 3a (Scheme 3a), which is probably due to the
strong binding ability of 15-crown-5 with the sodium cation. In
this case, the concentration of Na+ is decreased in the reaction
media, which led to a reduced reaction efficiency.16c,21
Meanwhile, when nBu4NOH was utilized, quinoxaline 3a
could not be detected, indicating that the alkali metal cation is
necessary for this reaction. Therefore, the hemiaminal working
model could be ruled out in the mechanism.16b The above
experiment reveals that the reaction rate was largely influenced
As shown in Table 1 (entries 1−5) and Table S1, base plays an
important role in determining the reaction efficiency. The
activity of redox condensation between 1a and 2a was strongly
dependent on the cation involved from LiOH (25%) to CsOH·
H2O (40%), KOH (49%), and NaOH (90%).16c,20a Meanwhile,
D
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Scheme 2. Gram-Scale Synthesis and Derivatization Reactions
reaction between nitrobenzene and benzyl alcohol was
investigated. To our delight, the desired product 11 was isolated
in 33% yields using 3.0 equiv NaOH (Scheme 3d).
Scheme 3. Control Experiments
Based on the above discussion and the relevant literature, a
plausible reaction mechanism was proposed (Scheme 4).
Initially, deprotonation of diol provided sodium salt A, which
underwent a redox reaction with o-nitroaniline 1a to afford o-
nitrosoaniline and α-hydroxy ketone 5a via the intermediate
TSB. The first reduction of NO2 to NO has also been verified by
DFT calculations, indicating that TSB could be the potential
intermediate (see the Supporting Information).23 Furthermore,
MPV-type HT between o-nitrosoaniline and sodium alkoxide C
via the intermediate TSD would generate diketone 10 and E,
which reacted with the hydroxyl group of the second diol to give
A and F. Another redox reaction between A and F would provide
benzene-1,2-diamine and α-hydroxy ketone 5a. Finally, the
base-induced intermolecular condensation between diamine
and 10 would give the desired quinoxaline 4a.
CONCLUSIONS
■
In conclusion, we have developed a novel and facile synthetic
methodology to efficiently access quinoxaline via a NaOH-
promoted redox-condensation strategy. During the reaction, o-
nitroanilines and alcohols serve as the hydrogen donors and
acceptors, respectively. The current protocol exhibits several
unique characteristics, such as a broad substrate scope, mild
reaction conditions, and being transition-metal-free. The
obtained quinoxalines could further undergo derivatization to
afford other value-added chemicals.
by the type of base and alkaline cations. The superiority of Na+
was also highlighted in previous report for the HT of ketones.20
However, it is still unclear for the mechanistic role of the metal
ions. Meanwhile, a relevant role is also played by the solvent,
with the apolar, nonprotic toluene affording the highest
conversion.22 Next, the reaction between 1a and α-hydroxy
ketone 5a gave product 4a and diketone 10 under the optimized
conditions. Meanwhile, condensation between o-diamine and
10 provided quinoxaline 4a in quantitative yield (Scheme 3b),
suggesting that benzene-1,2-diamine and diketone 10 might be
the potential intermediate. Finally, when o-nitroaniline 1a was
treated with diketone 10 or when diol was treated with o-
diamine, no corresponding product 4a could be detected
(Scheme 3c), implying the integral part of both the hydrogen
donor alcohol group and the hydrogen acceptor nitro group to
fulfill this transformation. To further verify the hypothesis, the
EXPERIMENTAL SECTION
■
General Experimental Details. Unless otherwise mentioned, all
reagents were obtained from commercial suppliers and used without
further purification. Phenyl-substituted diols and α-hydroxy ketones
were synthesized according to previous literature.24−26 Solvents were
dried with standard methods and freshly distilled prior to use if needed.
Melting points were determined on an XT4A melting point apparatus
and were uncorrected. Flash column chromatography was performed
using 200−300 mesh silica gel. Analytical and preparative thin-layer
chromatography (TLC) plates coated with commercial silica gel GF254
were used to monitor the reactions and purify the products. 1H NMR,
13C{H} NMR, and 19F{H} NMR spectra were recorded at 400 or 600
E
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Scheme 4. Proposed Reaction Mechanism
MHz, 101 or 151 MHZ, and 376 MHz, respectively, on a Bruker DPX
instrument using TMS as an internal standard. Data were reported as
follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, and m = multiplet), integration, and coupling
constants (J) in hertz. HRMS was performed on a Q-Tof micro LC/MS
system ESI spectrometer. ICP-AES analysis was conducted on a
Shimadzu multitype ICP emission spectrometer (213DFOG/ICP-
9820). ICP-MS analysis was conducted on the Agilent 7700s.
General Procedure for the Synthesis of 3 and 4. To an oven-
dried 35 mL Ace pressure tube was added 1 (0.5 or 0.1 mmol) or 6 (0.5
mmol), 2 or 5 (2.0 or 0.4 mmol), and NaOH in toluene (1.0 mL) under
Ar. The sealed tube was capped and taken out of the glovebox. After
stirring in a preheated oil bath at 120 °C for 3 h (or 150 °C for 12 h), the
reaction mixture was cooled down to room temperature and directly
concentrated under vacuum. The organic residue was purified by
preparative TLC to give the desired products 3 and 4.
2,3,6-Trimethylquinoxaline (3c). Purified by analytical TLC on
silica gel with DCM/EA (50:1) as an eluent Rf = 0.42; yellow solid (80.8
mg, 94%). mp: 89−90 °C. 1H NMR (400 MHz, CDCl3): δ 7.86 (d, J =
8.5 Hz, 1H), 7.75 (s, 1H), 7.49 (dd, J = 8.5, 1.7 Hz, 1H), 2.71 (s, 6H),
2.56 (s, 3H). 13C{H} NMR (101 MHz, CDCl3): δ 153.3, 152.4, 141.2,
139.1, 131.0, 127.8, 127.3, 23.2, 23.1, 21.7. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C11H13N2, 173.1073; found, 173.1072.
6-Fluoro-2,3-dimethylquinoxaline (3d). Purified by analytical TLC
on silica gel with DCM/EA (50:1) as an eluent Rf = 0.45; yellow solid
1
(54.0 mg, 61%). mp: 108−109 °C. H NMR (400 MHz, CDCl3): δ
7.97 (dd, J = 9.2, 5.7 Hz, 1H), 7.60 (dd, J = 9.3, 2.8 Hz, 1H), 7.35 (td, J =
8.6, 2.7 Hz, 1H), 2.72 (d, J = 3.0 Hz, 6H). 13C{H} NMR (101 MHz,
CDCl3): δ 162.1 (C−F, 1JC−F = 249.7 Hz), 154.5, 152.8 (C−F, 4JC−F
=
3.3 Hz), 141.7 (C−F, 3JC−F = 12.6 Hz), 138.2, 130.2 (C−F, 3JC−F = 9.8
Hz), 118.9 (C−F, 2JC−F = 25.7 Hz), 112.0 (C−F, 2JC−F = 21.4 Hz), 23.2,
23.0. 19F{H} NMR (376 MHz, CDCl3): δ −110.3. HRMS (ESI+,
MeOH) m/z: [M + H]+ calcd for C10H10FN2, 177.0823; found,
177.0823.
2,3-Dimethylquinoxaline (3a). Purified by analytical TLC on silica
gel with DCM/EA (50:1) as an eluent Rf = 0.28; brown solid (72.5 mg,
92% yield from o-nitroanilines; 32.4 mg, 41% yield from 1,2-
6-Chloro-2,3-dimethylquinoxaline (3e). Purified by analytical TLC
on silica gel with DCM/EA (50:1) as an eluent Rf = 0.48; white solid
(74.0 mg, 77%). mp: 89−90 °C. 1H NMR (400 MHz, CDCl3): δ 7.97
(d, J = 2.2 Hz, 1H), 7.91 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.3 Hz,
1H), 2.72 (d, J = 1.8 Hz, 6H). 13C{H} NMR (151 MHz, CDCl3): δ
154.6, 153.8, 141.2, 139.6, 134.4, 129.8, 129.6, 127.4, 23.2, 23.1. HRMS
(ESI+, MeOH) m/z: [M + H]+ calcd for C10H10ClN2, 193.0527; found,
193.0528.
6-Bromo-2,3-dimethylquinoxaline (3f). Purified by analytical TLC
on silica gel with DCM/EA (50:1) as an eluent Rf = 0.45; yellow solid
(96.8 mg, 82%). mp: 82−83 °C. 1H NMR (400 MHz, CDCl3): δ 8.15
(d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.73 (dd, J = 8.8, 2.1 Hz,
1H), 2.72 (d, J = 5.6 Hz, 6H). 13C{H} NMR (101 MHz, CDCl3): δ
154.5, 153.9, 141.8, 139.9, 132.2, 130.8, 129.7, 122.5, 23.2. HRMS
1
dinitrobenzene). mp: 91−92 °C. H NMR (400 MHz, CDCl3): δ
8.00−7.96 (m, 2H), 7.96−7.65 (m, 2H), 2.74 (s, 6H). 13C{H} NMR
(101 MHz, CDCl3): δ 153.5, 141.1, 128.8, 128.3, 23.2. HRMS (ESI+,
MeOH) m/z: [M + H]+ calcd for C10H11N2, 159.0917; found,
159.0915.
2,3,5-Trimethylquinoxaline (3b). Purified by analytical TLC on
silica gel with DCM/EA (50:1) as an eluent Rf = 0.49; yellow solid (76.5
mg, 89%). mp: 71−72 °C. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J =
8.1 Hz, 1H), 7.75−7.47 (m, 2H), 2.77 (s, 3H), 2.73 (s, 3H), 2.72 (s,
3H). 13C{H} NMR (101 MHz, CDCl3): δ 152.8, 152.2, 141.1, 140.3,
136.7, 128.8, 128.4, 126.1, 23.3, 23.1, 17.1. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C11H13N2, 173.1073; found, 173.1072.
F
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(ESI+, MeOH) m/z: [M + H]+ calcd for C10H10BrN2, 237.0022; found,
237.0023.
137.7, 131.7, 131.4, 130.4, 129.2, 123.7. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C20H13Br2N2, 438.9440; found, 438.9443.
2,3-Bis(3-methoxyphenyl)quinoxaline (4e). Purified by analytical
TLC on silica gel with PE/DCM (1:3) as an eluent Rf = 0.19; yellow
solid (133.6 mg, 98%). mp: 101−102 °C. 1H NMR (400 MHz,
CDCl3): δ 8.20−8.16 (m, 2H), 7.80−7.75 (m, 2H), 7.26−7.22 (m,
2H), 7.10−7.08 (m, 4H), 6.93−6.90 (m, 2H), 3.71 (s, 6H). 13C{H}
NMR (101 MHz, CDCl3): δ 159.5, 153.3, 141.2, 140.3, 130.0, 129.3,
129.2, 122.4, 115.2, 114.8, 55.3. HRMS (ESI+, MeOH) m/z: [M + H]+
calcd for C22H19N2O2, 343.1441; found, 343.1444.
6-Methoxy-2,3-dimethylquinoxaline (3g). Purified by analytical
TLC on silica gel with DCM/EA (8:1) as an eluent Rf = 0.17; orange
solid (77.5 mg, 82%). mp: 94−96 °C. 1H NMR (400 MHz, CDCl3): δ
7.86 (d, J = 8.8 Hz, 1H), 7.33−7.29 (m, 2H), 3.94 (s, 3H), 2.70 (d, J =
5.2 Hz, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 160.0, 153.4, 150.6,
142.5, 137.0, 129.3, 121.7, 106.2, 55.7, 23.1, 22.8. HRMS (ESI+,
MeOH) m/z: [M + H]+ calcd for C11H13N2O, 189.1022; found,
189.1023.
2,3-Dimethyl-6-(4-methylpiperazin-1-yl)quinoxaline (3h). Puri-
fied by column chromatography on alumina with EA as an eluent;
yellow solid (119.5 mg, 93%). mp: 115−116 °C. 1H NMR (400 MHz,
CDCl3): δ 7.82 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 9.4, 1.7 Hz, 1H), 7.23
(d, J = 2.7 Hz, 1H), 3.38 (t, J = 5.1 Hz, 4H), 2.67 (d, J = 3.8 Hz, 6H),
2.62 (t, J = 5.1 Hz, 4H), 2.37 (s, 3H). 13C{H} NMR (101 MHz,
CDCl3): δ 153.3, 151.3, 149.9, 142.5, 136.2, 128.6, 121.2, 109.6, 54.9,
48.7, 46.1, 23.1, 22.8. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C15H21N4, 257.1761; found, 257.1764.
7-Bromo-2,3,5-trimethylquinoxaline (3i). Purified by analytical
TLC on silica gel with DCM/EA (60:1) as an eluent Rf = 0.19; brown
solid (107.0 mg, 86%). mp: 63−65 °C. 1H NMR (400 MHz, CDCl3): δ
7.98 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 2.73 (s, 3H), 2.71 (s,
6H). 13C{H} NMR (151 MHz, CDCl3): δ 153.9, 152.6, 141.8, 139.1,
138.7, 132.0, 128.5, 122.1, 23.3, 23.1, 16.9. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C11H12BrN2, 251.0178; found, 251.0178.
2,3,6,7-Tetramethylquinoxaline (3j). Purified by analytical TLC on
silica gel with DCM/EA (50:1) as an eluent Rf = 0.38; yellow solid (87.5
mg, 94%). mp: 183−184 °C. 1H NMR (400 MHz, CDCl3): δ 7.72 (s,
2H), 2.69 (s, 6H), 2.46 (s, 6H). 13C{H} NMR (151 MHz, CDCl3): δ
152.3, 140.0, 139.0, 127.5, 23.1, 20.1. HRMS (ESI+, MeOH) m/z: [M +
H]+ calcd for C12H15N2, 187.1230; found, 187.1230.
6,7-Dichloro-2,3-dimethylquinoxaline (3k). Purified by analytical
TLC on silica gel with DCM/EA (50:1) as an eluent Rf = 0.58; brown
solid (71.5 mg, 63%). mp: 189−190 °C. 1H NMR (400 MHz, CDCl3):
δ 8.09 (s, 2H), 2.72 (s, 6H). 13C{H} NMR (101 MHz, CDCl3): δ
154.9, 139.9, 133.1, 129.1, 23.2. HRMS (ESI+, MeOH) m/z: [M + H]+
calcd for C10H9Cl2N2, 227.0137; found, 227.0135.
2,3-Diphenylquinoxaline (4a). Purified by analytical TLC on silica
gel with petroleum ether (PE)/DCM (1:1) as an eluent Rf = 0.40; white
solid [135.1 mg, 96% yield from o-nitroanilines and 1,2-diphenyl-
ethane-1,2-diol; 28.0 mg, 99% yield from o-nitroanilines and 1-(4-
bromophenyl)-2-hydroxyethan-1-one; 76.6 mg, 54% yield from 1,2-
dinitrobenzene and 1,2-diphenylethane-1,2-diol]. mp: 119−120 °C. 1H
NMR (600 MHz, CDCl3): δ 8.18 (dd, J = 6.3, 3.4 Hz, 2H), 7.78 (dd, J =
6.1, 3.2 Hz, 2H), 7.51 (d, J = 7.5 Hz, 4H), 7.38−7.32 (m, 6H). 13C{H}
NMR (151 MHz, CDCl3): δ 153.50, 141.3, 139.1, 130.0, 129.9, 129.2,
128.8, 128.3. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C20H15N2, 283.1230; found, 283.1231.
1,2,3,4-Tetrahydrophenazine (4f). Purified by analytical TLC on
silica gel with DCM/EA (50:1) as an eluent Rf = 0.43; yellow solid (69.1
mg, 75% yield from o-nitroanilines; 30.7 mg, 33% yield from 1,2-
1
dinitrobenzene). mp: 81−82 °C. H NMR (400 MHz, CDCl3): δ
8.00−7.91 (m, 2H), 7.69−7.65 (m, 2H), 3.20−3.16 (m, 4H), 2.07−
2.03 (m, 4H). 13C{H} NMR (101 MHz, CDCl3): δ 154.1, 141.1, 129.0,
128.3, 33.1, 22.8. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C12H13N2, 185.1073; found, 185.1072.
2-Phenylquinoxaline (4g). Purified by analytical TLC on silica gel
with DCM as an eluent Rf = 0.55; yellow solid (74.2 mg, 72% yield from
1-phenylethane-1,2-diol; 12.6 mg, 61% yield from 2-hydroxy-1-
phenylethan-1-one). mp: 71−72 °C. 1H NMR (400 MHz, CDCl3): δ
9.34 (s, 1H), 8.22−8.12 (m, 4H), 7.82−7.73 (m, 2H), 7.60−7.51 (m,
3H). 13C{H} NMR (101 MHz, CDCl3): δ 151,5, 143.4, 142.3, 141.6,
136.8, 130.3, 130.2, 129.7, 129.6, 129.2, 127.6. HRMS (ESI+, MeOH)
m/z: [M + H]+ calcd for C14H11N2, 207.0917; found, 207.0918.
2-(p-Tolyl)quinoxaline (4h). Purified by analytical TLC on silica gel
with PE/EA (10:1) as an eluent Rf = 0.33; yellow solid [15.4 mg, 70%
yield from 1-(p-tolyl)ethane-1,2-diol; 11.1 mg, 50% yield from 2-
hydroxy-1-(p-tolyl)ethan-1-one]. mp: 85−86 °C. 1H NMR (400 MHz,
CDCl3): δ 9.31 (s, 1H), 8.16−8.10 (m, 4H), 7.80−7.71 (m, 2H), 7.37
(d, J = 8.0 Hz, 2H), 2.46 (s, 3H). 13C{H} NMR (101 MHz, CDCl3): δ
151.9, 143.3, 142.4, 141.5, 140.5, 134.0, 129.9, 129.6, 129.3, 129.1,
127.4, 21.4. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C15H13N2,
221.1073; found, 221.1076.
2-(4-Chlorophenyl)quinoxaline (4i). Purified by analytical TLC on
silica gel with PE/EA (10:1) as an eluent Rf = 0.31; brown solid [17.5
mg, 73% yield from 1-(4-chlorophenyl)ethane-1,2-diol; 13.2 mg, 55%
yield from 1-(4-chlorophenyl)-2-hydroxyethan-1-one]. mp: 112−113
°C. 1H NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.171−8.12 (m, 4H),
7.82−7.74 (m, 2H), 7.55−7.52 (m, 2H). 13C{H} NMR (101 MHz,
CDCl3): δ 150.6, 142.9, 142.2, 141.7, 136.6, 135.2, 130.5, 129.8, 129.6,
129.4, 129.2, 128.8. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C14H10ClN2, 241.0527; found, 241.0530.
2-(4-Bromophenyl)quinoxaline (4j). Purified by analytical TLC on
silica gel with PE/EA (10:1) as an eluent Rf = 0.26; yellow solid [20.2
mg, 71% yield from 1-(4-bromophenyl)ethane-1,2-diol; 15.6 mg, 55%
yield from 1-(4-bromophenyl)-2-hydroxyethan-1-one]. mp: 132−133
°C. 1H NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 8.19 (dd, J = 8.2, 1.7
Hz, 2H), 8.15 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 8.9 Hz, 1H), 7.68 (dd, J =
8.9, 2.3 Hz, 1H), 7.60−7.52 (m, 3H). 13C{H} NMR (101 MHz,
CDCl3): δ 150.6, 142.8, 142.2, 141.7, 135.6, 132.4, 129.8, 129.6, 129.2,
125.0. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C14H10BrN2,
285.0022; found, 285.0024.
2-Methylquinoxaline (4k). Purified by analytical TLC on silica gel
with DCM/EA (50:1) as an eluent Rf = 0.51; yellow liquid (35.3 mg,
48% yield from propane-1,2-diol; 6.4 mg, 44% yield from 1-
hydroxypropan-2-one). 1H NMR (400 MHz, CDCl3): δ 8.75 (s,
1H), 8.09−8.06 (m, 1H), 8.03−8.01 (m, 1H), 7.77−7.69 (m, 2H), 2.79
(s, 3H). 13C{H} NMR (101 MHz, CDCl3): δ 153.8, 146.0, 142.1,
141.0, 130.0, 129.2, 128.9, 128.7, 22.6. HRMS (ESI+, MeOH) m/z: [M
+ H]+ calcd for C9H9N2, 145.0760; found, 145.0759.
2,3-Di-p-tolylquinoxaline (4b). Purified by analytical TLC on silica
gel with PE/DCM (2:1) as an eluent Rf = 0.15; yellow solid (21.4 mg,
69% yield from 1,2-di-p-tolylethane-1,2-diol; 30.1 mg, 99% yield from
2-hydroxy-1,2-di-p-tolylethan-1-one). mp: 136−137 °C. 1H NMR (400
MHz, CDCl3): δ 8.17−8.13 (m, 2H), 7.76−7.72 (m, 2H), 7.43 (d, J =
8.0 Hz, 4H), 7.15 (d, J = 8.0 Hz, 4H), 2.37 (s, 6H). 13C{H} NMR (101
MHz, CDCl3): δ 153.5, 141.2, 138.8, 136.4, 129.72, 129.65, 129.1,
+
129.0, 21.4. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C22H19N2 ,
311.1543; found, 311.1545.
2,3-Bis(4-chlorophenyl)quinoxaline (4c). Purified by analytical
TLC on silica gel with PE/DCM (1:1) as an eluent Rf = 0.50; yellow
solid (91.0 mg, 52%). mp: 176−177 °C. 1H NMR (400 MHz, CDCl3):
δ 8.18−8.14 (m, 2H), 7.82−7.77 (m, 2H), 7.49−7.45 (m, 4H), 7.36−
7.33 (m, 4H). 13C{H} NMR (101 MHz, CDCl3): δ 151.9, 141.3, 137.3,
135.4, 131.2, 130.4, 129.2, 128.7. HRMS (ESI+, MeOH) m/z: [M +
H]+ calcd for C20H13Cl2N2, 351.0450; found, 351.0452.
2,3-Bis(4-bromophenyl)quinoxaline (4d). Purified by analytical
TLC on silica gel with PE/DCM (3:2) as an eluent Rf = 0.22; yellow
solid (24.0 mg, 55%). mp: 186−187 °C. 1H NMR (400 MHz, CDCl3):
δ 8.17−8.14 (m, 2H), 7.82−7.78 (m, 2H), 7.51 (d, J = 8.5 Hz, 4H), 7.41
(d, J = 8.5 Hz, 4H). 13C{H} NMR (101 MHz, CDCl3): δ 151.9, 141.3,
2-Ethylquinoxaline (4l). Purified by analytical TLC on silica gel with
DCM/EA (50:1) as an eluent Rf = 0.39; yellow liquid (41.8 mg, 53%).
1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.09−8.04 (m, 2H),
7.77−7.69 (m, 2H), 3.07 (q, J = 7.6 Hz, 2H), 1.45 (t, J = 7.6 Hz, 3H).
13C{H} NMR (101 MHz, CDCl3): δ 158.5, 145.6, 142.2, 141.3, 129.9,
129.2, 128.91, 128.88, 29.6, 13.4. HRMS (ESI+, MeOH) m/z: [M +
H]+ calcd for C10H11N2, 159.0917; found, 159.0923.
G
https://dx.doi.org/10.1021/acs.joc.0c02453
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
2-Propylquinoxaline (4m). Purified by analytical TLC on silica gel
with DCM/EA (50:1) as an eluent Rf = 0.74; yellow liquid (48.2 mg,
55%). H NMR (400 MHz, CDCl3): δ 8.75 (s, 1H), 8.09−8.03 (m,
2H), 7.77−7.69 (m, 2H), 3.00 (t, J = 7.7 Hz, 2H), 1.94−1.83 (m, 2H),
1.05 (t, J = 7.4 Hz, 3H). 13C{H} NMR (101 MHz, CDCl3): δ 157.5,
145.9, 142.2, 141.2, 129.9, 129.2, 128.91, 128.88, 38.4, 22.8, 13.9.
HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C11H13N2, 173.1073;
found, 173.1075.
2-Butylquinoxaline (4n). Purified by analytical TLC on silica gel
with PE/EA (10:1) as an eluent Rf = 0.44; yellow liquid (75.6 mg, 81%).
1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.07−8.02 (m, 2H),
7.74−7.66 (m, 2H), 3.00 (t, J = 7.8 Hz, 2H), 1.86−1.79 (m, 2H), 1.50−
1.40 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{H} NMR (151 MHz,
CDCl3): δ 157.7, 145.8, 142.2, 141.2, 129.9, 129.2, 128.9, 36.2, 31.6,
22.6, 13.9. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C12H15N2,
187.1230; found, 187.1231.
2-Hexylquinoxaline (4o). Purified by analytical TLC on silica gel
with PE/EA (10:1) as an eluent Rf = 0.48; yellow liquid (87.8 mg, 82%).
1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.08−8.02 (m, 2H),
7.75−7.67 (m, 2H), 3.00 (t, J = 7.7 Hz, 2H), 1.88−1.80 (m, 2H), 1.44−
1.39 (m, 2H), 1.37−1.28 (m, 4H), 1.88 (t, J = 7.2 Hz, 3H). 13C{H}
NMR (151 MHz, CDCl3): δ 157.7, 145.8, 142.2, 141.2, 129.9, 129.2,
128.9, 36.5, 31.6, 29.5, 22.5, 14.0. HRMS (ESI+, MeOH) m/z: [M +
H]+ calcd for C14H19N2, 215.1543; found, 215.1546.
7.85 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.14 (m,
4H), 2.56 (s, 3H), 2.03 (m, 4H). 13C{H} NMR (151 MHz, CDCl3): δ
154.0, 153.1, 141.3, 139.7, 139.2, 131.2, 127.9, 127.3, 33.2, 33.1, 22.88,
22.87, 21.8. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C13H15N2,
199.1230; found, 199.1232.
1
7-Chloro-1,2,3,4-tetrahydrophenazine (4v). Purified by analytical
TLC on silica gel with DCM/EA (50:1) as an eluent Rf = 0.50; brown
solid (63.6 mg, 58% yield from 4-chloro-2-nitroaniline; 75.0 mg, 69%
1
yield from 5-chloro-2-nitroaniline). mp: 91−92 °C. H NMR (600
MHz, CDCl3): δ 7.96 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.7
Hz, 1H), 3.15 (m, 4H), 2.04 (m, 4H). 13C{H} NMR (151 MHz,
CDCl3): δ 155.3, 154.5, 141.5, 139.7, 134.5, 129.9, 129.6, 127.4, 33.21,
33.16, 22.70, 22.68. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C12H12ClN2, 219.0684; found, 219.0683.
7,8-Dimethyl-1,2,3,4-tetrahydrophenazine (4w). Purified by ana-
lytical TLC on silica gel with DCM/EA (50:1) as an eluent Rf = 0.40;
yellow solid (74.2 mg, 70%). mp: 143−145 °C. 1H NMR (600 MHz,
CDCl3): δ 7.70 (s, 2H), 3.13 (m, 4H), 2.46 (s, 6H), 2.02 (m, 4H).
13C{H} NMR (151 MHz, CDCl3): δ 153.0, 140.2, 139.2, 127.5, 33.1,
22.9, 20.3. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C14H17N2,
213.1386; found, 213.1386.
8-Bromo-6-methyl-1,2,3,4-tetrahydrophenazine (4x). Purified by
analytical TLC on silica gel with PE/DCM (1:1) as an eluent Rf = 0.33;
1
yellow solid (70.7 mg, 51%). mp: 63−65 °C. H NMR (400 MHz,
2-(Naphthalen-2-yl)quinoxaline (4p). Purified by analytical TLC
on silica gel with PE/EA (10:1) as an eluent Rf = 0.30; yellow solid
CDCl3): δ 7.98 (d, J = 1.8 Hz, 1H), 7.59 (d, J = 1.1 Hz, 1H), 3.15−3.12
(m, 4H), 2.73 (s, 3H), 2.05−2.01 (m, 4H). 13C{H} NMR (151 MHz,
CDCl3): δ 154.6, 153.4, 141.9, 139.3, 138.7, 132.1, 128.5, 122.2, 33.4,
33.1, 22.8, 17.0. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C13H14BrN2, 277.0335; found, 277.0340.
1
(20.5 mg, 80%). mp: 126−127 °C. H NMR (400 MHz, CDCl3): δ
9.48 (s, 1H), 8.66 (s, 1H), 8.36 (dd, J = 8.6, 1.8 Hz, 1H), 8.21−8.19 (m,
1H), 8.16−8.13 (m, 1H), 8.04−8.00 (m, 2H), 7.92−7.90 (m, 1H),
7.83−7.73 (m, 2H), 7.59−7.54 (m, 2H). 13C{H} NMR (101 MHz,
CDCl3): δ 151.7, 143.5, 142.4, 141.6, 134.2, 134.1, 133.4, 130.4, 129.7,
129.6, 129.2, 129.1, 128.9, 127.8, 127.5, 127.3, 126.7, 124.5. HRMS
(ESI+, MeOH) m/z: [M + H]+ calcd for C18H13N2, 257.1073; found,
257.1076.
6,7-Dimethyl-2-phenylquinoxaline (4y). Purified by analytical TLC
on silica gel with DCM/EA (50:1) as an eluent Rf = 0.64; white solid
1
(93.5 mg, 80%). mp: 128−130 °C. H NMR (400 MHz, CDCl3): δ
9.22 (s, 1H), 8.18−8.16 (m, 2H), 7.91 (s, 1H), 7.86 (s, 1H), 7.58−7.48
(m, 3H), 2.51 (s, 6H). 13C{H} NMR (151 MHz, CDCl3): δ 151.0,
142.4, 141.3, 140.8, 140.6, 140.1, 137.2, 129.8, 129.1, 128.7, 128.2,
127.4, 20.4, 20.3. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C16H15N2, 235.1230; found, 235.1230.
6-Methyl-2,3-diphenylquinoxaline (4q). Purified by analytical TLC
on silica gel with PE/DCM (1:1) as an eluent Rf = 0.48; white solid
(136.6 mg, 92%). mp: 111−112 °C. 1H NMR (400 MHz, CDCl3): δ
8.06 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.61(dd, J = 8.6, 1.8 Hz, 1H),
7.52−7.49 (m, 4H), 7.36−7.30 (m, 6H), 2.62 (s, 3H). 13C{H} NMR
(101 MHz, CDCl3): δ 153.3, 152.6, 141.3, 140.5, 139.7, 139.2, 132.3,
129.9, 129.8, 128.73, 128.70, 128.6, 128.2, 128.0, 21.9. HRMS (ESI+,
MeOH) m/z: [M + H]+ calcd for C21H17N2, 297.1387; found,
297.1387.
6-Chloro-2,3-diphenylquinoxaline (4r). Purified by analytical TLC
on silica gel with PE/DCM (2:1) as an eluent Rf = 0.18; white solid
(145.7 mg, 92% yield from 4-chloro-2-nitroaniline; 153.6 mg, 97% yield
from 5-chloro-2-nitroaniline). mp: 110−111 °C. 1H NMR (400 MHz,
CDCl3): δ 8.15 (d, J = 2.2 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.68 (dd, J
= 8.9, 2.3 Hz, 1H), 7.51−7.49 (m, 4H), 7.38−7.30 (m, 6H). 13C{H}
NMR (101 MHz, CDCl3): δ 154.3, 153.6, 141.5, 139.7, 138.8, 138.7,
135.7, 131.0, 130.5, 129.9, 129.8, 129.1, 129.0, 128.35, 128.34, 128.1.
HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C20H14ClN2,
317.0840; found, 317.0840.
6,7-Dimethyl-2,3-diphenylquinoxaline (4s). Purified by analytical
TLC on silica gel with PE/DCM (1:1) as an eluent Rf = 0.38; white
solid (152.0 mg, 98%). mp: 176−177 °C. 1H NMR (400 MHz,
CDCl3): δ 7.92 (s, 2H), 7.51−7.49 (m, 4H), 7.35−7.29 (m, 6H), 2.52
(s, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 152.5, 140.5, 140.2,
139.4, 129.9, 128.5, 128.23, 128.20, 20.4. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C22H19N2, 311.1543; found, 311.1541.
6,7-Dichloro-2,3-diphenylquinoxaline (4t). Purified by analytical
TLC on silica gel with PE/DCM (2:1) as an eluent Rf = 0.28; white
solid (140.2 mg, 80%). mp: 138−139 °C. 1H NMR (600 MHz,
CDCl3): δ 8.29 (s, 2H), 7.50 (d, J = 7.5 Hz, 4H), 7.40−7.33 (m, 6H).
13C{H} NMR (101 MHz, CDCl3): δ 154.5, 140.0, 138.4, 134.4, 129.8,
129.3, 128.4. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C20H13Cl2N2, 351.0450; found, 351.0452.
6,7-Dichloro-2-phenylquinoxaline (4z). Purified by analytical TLC
on silica gel with PE/EA (15:1) as an eluent Rf = 0.53; yellow solid
1
(63.0 mg, 46%). mp: 155−157 °C. H NMR (400 MHz, CDCl3): δ
9.32 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.20−8.18 (m, 2H), 7.61−7.55
(m, 3H). 13C{H} NMR (101 MHz, CDCl3): δ 152.7, 144.3, 141.1,
140.3, 136.0, 134.9, 134.0, 130.9, 130.2, 129.8, 129.3, 127.6. HRMS
(ESI+, MeOH) m/z: [M + H]+ calcd for C14H9Cl2N2, 275.0137; found,
275.0142.
2,3-Bis(4-methoxyphenyl)quinoxaline (4aa). Purified by analytical
TLC on silica gel with PE/DCM (1:3) as an eluent Rf = 0.21; yellow
solid (34.0 mg, 99% yield from o-nitroanilines; 89.2 mg, 52% yield from
1
1,2-dinitrobenzene). mp: 143 °C. H NMR (400 MHz, CDCl3): δ
8.14−8.10 (m, 2H), 7.73−7.69 (m, 2H), 7.51−7.48 (m, 4H), 6.89−
6.85 (m, 4H), 3.82 (s, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 160.2,
153.0, 141.1, 131.8, 131.3, 129.5, 129.0, 113.8, 55.3. HRMS (ESI+,
MeOH) m/z: [M + H]+ calcd for C22H19N2O2, 343.1441; found,
343.1444.
2,3-Di(furan-2-yl)quinoxaline (4ab). Purified by analytical TLC on
silica gel with PE/DCM (1:3) as an eluent Rf = 0.42; brown solid (25.9
1
mg, 99%). mp: 122−123 °C. H NMR (400 MHz, CDCl3): δ 8.16−
8.12 (m, 2H), 7.77−7.32 (m, 2H), 7.63 (dd, J = 1.7, 0.67 Hz, 2H), 6.66
(dd, J = 3.5, 0.52 Hz, 2H), 6.57 (dd, J = 3.5, 1.7 Hz, 2H). 13C{H} NMR
(101 MHz, CDCl3): δ 150.8, 144.2, 142.7, 140.6, 130.4, 129.1, 113.0,
111.9. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C16H11N2O2,
263.0815; found, 263.0818.
2,3-Bis(4-methoxyphenyl)-6-methylquinoxaline (4ac). Purified by
analytical TLC on silica gel with PE/DCM (1:3) as an eluent Rf = 0.23;
yellow solid (31.6 mg, 88%). mp: 118−119 °C. 1H NMR (400 MHz,
CDCl3): δ 8.01 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.55 (dd, J = 6.8, 1.8
Hz, 1H), 7.50−7.46 (m, 4H), 6.88−6.85 (m, 4H), 3.82 (s, 6H), 2.59 (s,
3H). 13C{H} NMR (101 MHz, CDCl3): δ 160.1, 160.0, 152.9, 152.2,
141.1, 140.0, 139.5, 131.91, 131.86, 131.2, 128.5, 127.9, 113.8, 113.7,
7-Methyl-1,2,3,4-tetrahydrophenazine (4u). Purified by analytical
TLC on silica gel with DCM/EA (50:1) as an eluent Rf = 0.35; yellow
solid (79.2 mg, 80%). mp: 80−81 °C. 1H NMR (600 MHz, CDCl3): δ
H
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55.3, 21.9. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C23H21N2O2, 357.1598; found, 357.1062.
Procedure for the Preparation of 2,3-Dimethyl-1,2,3,4-
tetrahydroquinoxaline 8. To a Schlenk tube were added 3a (39.5
mg, 0.25 mmol) and AgOTf (3.2 mg, 0.0125 mmol) in deionized water
(1.0 mL). PhSiH3 (108.0 mg, 1.0 mmol) was added dropwise using a
syringe over 1 min under air. The reaction mixture was stirred at room
temperature for 30 min, diluted with deionized water (5.0 mL), and
extracted with ethyl acetate (3 × 5 mL). After removal of the organic
solvent, the residue was purified by preparative TLC on silica gel plates
using PE/EA (10:1) as the eluent to give product 8 in 88% yield. Rf =
6-Chloro-2,3-bis(4-methoxyphenyl)quinoxaline (4ad). Purified by
analytical TLC on silica gel with PE/DCM (1:3) as an eluent Rf = 0.38;
yellow solid (33.5 mg, 89% yield from 4-chloro-2-nitroaniline; 37.2 mg,
1
98% yield from 5-chloro-2-nitroaniline). mp: 147−148 °C. H NMR
(400 MHz, CDCl3): δ 8.10 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H),
7.64 (dd, J = 8.5, 2.3 Hz, 1H), 7.50−7.46 (m, 4H), 6.89−6.85 (m, 4H),
3.83 (s, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 160.4, 160.3, 153.8,
153.2, 141.3, 139.5, 135.1, 131.38, 131.30, 131.28, 131.23, 130.5, 130.2,
127.9, 113.84, 113.83, 55.3. HRMS (ESI+, MeOH) m/z: [M + H]+
calcd for C22H18ClN2O2, 377.1051; found, 377.1054.
1
0.16; yellow solid (35.8 mg, 88%). mp: 104−106 °C. H NMR (400
MHz, CDCl3): δ 6.59−6.56 (m, 2H), 6.51−6.48 (m, 2H), 3.48 (q, J =
5.7 Hz, 2H), 3.36 (s, 2H), 1.11 (d, J = 6.4 Hz, 6H). 13C{H} NMR (101
MHz, CDCl3): δ 132.6, 118.6, 114.5, 49.1, 17.2. HRMS (ESI+, MeOH)
m/z: [M + H]+ calcd for C10H15N2, 163.1230; found, 163.1227.
Procedure for the Preparation of 2,3-Diphenethylquinoxa-
line 9. To an oven-dried 35 mL Ace pressure tube were added 3a (39.5
mg, 0.25 mmol), benzyl alcohol (108.1 mg, 1.0 mmol), KOtBu (14.0
mg, 0.125 mmol), NiBr2 (5.5 mg, 0.025 mmol), and 1,10-phenanthro-
line (22.5 mg, 0.13 mmol) in toluene (2.0 mL) under Ar. The sealed
tube was capped and taken out of a glovebox. After stirring in a
preheated oil bath at 140 °C for 12 h, the reaction mixture was cooled
down to room temperature and directly concentrated under vacuum.
The residue was purified by preparative TLC on silica gel plates using
PE/EA (5:1) as the eluent to give product 9 in 96% yield. Rf = 0.63;
6-Methoxy-2,3-bis(4-methoxyphenyl)quinoxaline (4ae). Purified
by analytical TLC on silica gel with PE/DCM (1:3) as an eluent Rf =
1
0.10; yellow solid (36.6 mg, 98% yield). mp: 126−127 °C. H NMR
(400 MHz, CDCl3): δ 8.01 (d, J = 9.1 Hz, 1H), 7.49−7.42 (m, 5H),
7.37 (dd, J = 9.1, 2.8 Hz, 1H), 6.89−6.84 (m, 4H), 3.97 (s, 3H), 3.82 (d,
J = 1.4 Hz, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 160.9, 160.1,
159.9, 152.9, 150.6, 142.6, 137.2, 131.92, 131.90, 131.2, 131.1, 130.0,
122.8, 113.8, 106.4, 55.8, 55.3. HRMS (ESI+, MeOH) m/z: [M + H]+
calcd for C23H21N2O3, 373.1547; found, 373.1550.
6,7-Dichloro-2,3-bis(4-methoxyphenyl)quinoxaline (4af). Puri-
fied by analytical TLC on silica gel with PE/DCM (1:3) as an eluent
1
Rf = 0.54; yellow solid (36.9 mg, 90%). mp: 156−157 °C. H NMR
1
yellow solid (81.6 mg, 96%). H NMR (400 MHz, CDCl3): δ 8.07−
(400 MHz, CDCl3): δ 8.21 (s, 2H), 7.50−7.46 (m, 4H), 6.89−6.85 (m,
4H), 3.83 (s, 6H). 13C{H} NMR (101 MHz, CDCl3): δ 160.6, 154.0,
139.8, 133.8, 131.3, 131.0, 129.6, 113.9, 55.3. HRMS (ESI+, MeOH)
m/z: [M + H]+ calcd for C22H17Cl2N2O2, 411.0662; found, 411.0661.
6-Chloro-2,3-di(furan-2-yl)quinoxaline (4ag). Purified by analyt-
ical TLC on silica gel with PE/EA (10:1) as an eluent Rf = 0.33; brown
solid (27.5 mg, 93% yield from 4-chloro-2-nitroaniline; 23.9 mg, 81%
yield from 5-chloro-2-nitroaniline). mp: 108−109 °C. 1H NMR (400
MHz, CDCl3): δ 8.12 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.67
(dd, J = 9.0, 2.2 Hz, 1H), 7.63−7.62 (m, 2H) 6.71−6.70 (m, 2H), 6.57
(dd, J = 3.5, 1.7 Hz, 2H). 13C{H} NMR (101 MHz, CDCl3): δ 150.6,
150.5, 144.6, 144.4, 143.3, 142.6, 140.9, 139.1, 136.2, 131.3, 130.3,
128.0, 113.7, 113.4, 112.1, 112.0. HRMS (ESI+, MeOH) m/z: [M +
H]+ calcd for C16H10ClN2O2, 297.0425; found, 297.0428.
8.03 (m, 2H), 7.71−7.67 (m, 2H), 7.30−7.26 (m, 4H), 7.22−7.18 (m,
6H), 3.26−3.21 (m, 4H), 3.17−3.13 (m, 4H). 13C{H} NMR (101
MHz, CDCl3): δ 155.4, 141.5, 141.0, 129.0, 128.6, 128.52, 128.51,
126.2, 37.0, 34.3. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C24H23N2, 339.1856; found, 339.1858.
Gram-Scale Synthesis. To a 250 mL round-bottom flask equipped
with a Dean−Stark apparatus were added 1a (13.8 g, 100 mmol), 2a
(36.0 g, 400 mmol), and NaOH (2.00 g, 50 mol %) in toluene (100 mL)
under Ar. The mixture was refluxed in a preheated oil bath for 4 h and
cooled down to ambient temperature afterward. After the removal of
organic solvent, water (100 mL) was added and extracted with ethyl
acetate (3 × 150 mL). The combined organic layer was dried over
anhydrous MgSO4 and concentrated under vacuum. The residue was
purified through a silica gel column using DCM as the eluent to give
pure sulfonylated product 3a in 87% (13.7 g) isolated yield.
2,3-Di(furan-2-yl)-6-methoxyquinoxaline (4ah). Purified by ana-
lytical TLC on silica gel with PE/EA (10:1) as an eluent Rf = 0.15;
brown solid (22.9 mg, 78%). mp: 105−106 °C. 1H NMR (400 MHz,
CDCl3): δ 8.01 (d, J = 9.2 Hz, 1H), 7.63−7.60 (m, 2H), 7.45 (d, J = 2.7
Hz, 1H), 7.39 (dd, J = 9.2, 2.7 Hz, 1H), 6.66 (dd, J = 3.4, 0.62 Hz, 1H),
6.56 (dd, J = 3.4, 1.8 Hz, 1H), 6.54 (d, J = 1.2 Hz, 2H), 3.97 (s, 3H).
13C{H} NMR (101 MHz, CDCl3): δ 161.4, 151.0, 150.8, 144.2, 143.7,
142.7, 142.4, 140.2, 136.7, 130.1, 123.9, 113.0, 112.0, 111.9, 111.8
106.5, 55.9. HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for
C17H13N2O3, 293.0921; found, 293.0924.
6,7-Dichloro-2,3-di(furan-2-yl)quinoxaline (4ai). Purified by ana-
lytical TLC on silica gel with PE/EA (10:1) as an eluent Rf = 0.37;
brown solid (24.8 mg, 75%). mp: 136−138 °C. 1H NMR (400 MHz,
CDCl3): δ 8.23 (s, 2H), 7.63 (dd, J = 1.7, 0.62 Hz, 2H), 6.73 (dd, J =
3.5, 0.63 Hz, 2H), 6.58 (dd, J = 3.5, 1.7 Hz, 2H). 13C{H} NMR (101
MHz, CDCl3): δ 150.3, 144.7, 143.3, 139.3, 134.8, 129.6, 113.9, 112.1.
HRMS (ESI+, MeOH) m/z: [M + H]+ calcd for C16H9Cl2N2O2,
331.0036; found, 331.0039.
Procedure for the Preparation of 3-Methylquinoxaline-2-
carbaldehyde 7. To a mixture solution of dioxane/H2O (5:1, 12 mL)
were added 3a (158.2 mg, 1.0 mmol) and selenium dioxide (111.9 mg,
1.3 mmol). After refluxing in a preheated oil bath for 12 h, water (8 mL)
was added and extracted with ethyl acetate (3 × 10 mL). The combined
organic layer was dried over anhydrous MgSO4 and concentrated under
vacuum. The residue was purified by preparative TLC on silica gel
plates using PE/EA (10:1) as the eluent to give product 7 in 67% yield.
Rf = 0.37; yellow solid (116.2 mg, 67%). mp: 136−138 °C. 1H NMR
(400 MHz, CDCl3): δ 10.32 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 8.09 (d, J
= 8.5 Hz, 1H), 7.92−7.88 (m, 1H), 7.81 (t, J = 7.5 Hz, 1H), 3.05 (s,
3H). 13C{H} NMR (101 MHz, CDCl3): δ 194.0, 153.6, 145.2, 142.8,
140.8, 133.0, 130.00, 129.98, 128.6, 23.3. HRMS (ESI+, MeOH) m/z:
[M + H]+ calcd for C10H9N2O, 173.0709; found, 173.0708.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02453.
■
sı
Optimization of reaction conditions, ICP analysis,
mechanistic studies, and NMR spectra of compounds
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Xinju Zhu − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0003-1966-3480; Email: zhuxinju@zzu.edu.cn
Mao-Ping Song − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0003-3883-2622; Email: mpsong@zzu.edu.cn
Authors
Yan-Bing Wang − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Linlin Shi − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Xiaojie Zhang − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Lian-Rong Fu − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
I
https://dx.doi.org/10.1021/acs.joc.0c02453
J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
of N-Aryl Enamines with Nitromethane toward 3-(Trifluoromethyl)-
quinoxalines. Chem. Commun. 2014, 50, 14554−14557. (c) Chen, F.;
Huang, X.; Li, X.; Shen, T.; Zou, M.; Jiao, N. Dehydrogenative N-
Incorporation: A Direct Approach to Quinoxaline N-Oxides under
Mild Conditions. Angew. Chem., Int. Ed. 2014, 53, 10495−10499.
(6) (a) Leifert, D.; Studer, A. Iodinated (Perfluoro)alkyl Quinoxalines
by Atom Transfer Radical Addition Using ortho-Diisocyanoarenes as
Radical Acceptors. Angew. Chem., Int. Ed. 2016, 55, 11660−11663.
(b) Sun, X.; Wang, W.; Li, Y.; Ma, J.; Yu, S. Halogen-Bond-Promoted
Double Radical Isocyanide Insertion under Visible-Light Irradiation:
Synthesis of 2-Fluoroalkylated Quinoxalines. Org. Lett. 2016, 18,
4638−4641.
Weinan Hu − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China
Wenjing Zhang − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0001-7964-6792
Xin-Qi Hao − College of Chemistry, Zhengzhou University,
Zhengzhou, Henan 450001, P. R. China; orcid.org/0000-
0003-1942-8309
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02453
(7) (a) Sato, H.; Turnbull, B. W. H.; Fukaya, K.; Krische, M. J.
Ruthenium(0)-Catalyzed Cycloaddition of 1,2-Diols, Ketols, or Diones
via Alcohol-Mediated Hydrogen Transfer. Angew. Chem., Int. Ed. 2018,
57, 3012−3021. (b) Corma, A.; Navas, J.; Sabater, M. J. Advances in
One-Pot Synthesis through Borrowing Hydrogen Catalysis. Chem. Rev.
2018, 118, 1410−1459. (c) Irrgang, T.; Kempe, R. 3d-Metal Catalyzed
N- and C-Alkylation Reactions via Borrowing Hydrogen or Hydrogen
Autotransfer. Chem. Rev. 2019, 119, 2524−2549. (d) Wang, D.; Zhao,
K.; Xu, C.; Miao, H.; Ding, Y. Synthesis, Structures of Benzoxazolyl
Iridium(III) Complexes, and Applications on C−C and C−N Bond
Formation Reactions under Solvent-Free Conditions: Catalytic Activity
Enhanced by Noncoordinating Anion without Silver Effect. ACS Catal.
2014, 4, 3910−3918.
(8) (a) Gunanathan, C.; Milstein, D. Applications of Acceptorless
Dehydrogenation and Related Transformations in Chemical Synthesis.
Science 2013, 341, 1229712. (b) Yang, Q.; Wang, Q.; Yu, Z.
Substitution of Alcohols by N-nucleophiles via Transition Metal-
Catalyzed Dehydrogenation. Chem. Soc. Rev. 2015, 44, 2305−2329.
(c) Ma, X.; Su, C.; Xu, Q. N-Alkylation by Hydrogen Autotransfer
Reactions. Top. Curr. Chem. 2016, 374, 27.
(9) (a) Nandakumar, A.; Midya, S. P.; Landge, V. G.; Balaraman, E.
Transition-Metal-Catalyzed Hydrogen-Transfer Annulations: Access
to Heterocyclic Scaffolds. Angew. Chem., Int. Ed. 2015, 54, 11022−
11034. (b) Crabtree, R. H. Homogeneous Transition Metal Catalysis of
Acceptorless Dehydrogenative Alcohol Oxidation: Applications in
Hydrogen Storage and to Heterocycle Synthesis. Chem. Rev. 2017, 117,
9228−9246. (c) Filonenko, G. A.; van Putten, R.; Hensen, E. J. M.;
Pidko, E. A. Catalytic (De)hydrogenation Promoted by Non-precious
Metals-Co, Fe and Mn: Recent Advances in An Emerging Field. Chem.
Soc. Rev. 2018, 47, 1459−1483.
(10) (a) Hille, T.; Irrgang, T.; Kempe, R. The Synthesis of
Benzimidazoles and Quinoxalines from Aromatic Diamines and
Alcohols by Iridium-Catalyzed Acceptorless Dehydrogenative Alkyla-
tion. Chem.Eur. J. 2014, 20, 5569−5572. (b) Daw, P.; Kumar, A.;
Espinosa-Jalapa, N. A.; Diskin-Posner, Y.; Ben-David, Y.; Milstein, D.
Synthesis of Pyrazines and Quinoxalines via Acceptorless Dehydrogen-
ative Coupling Routes Catalyzed by Manganese Pincer Complexes.
ACS Catal. 2018, 8, 7734−7741. (c) Shee, S.; Ganguli, K.; Jana, K.;
Kundu, S. Cobalt Complex Catalyzed Atom-economical Synthesis of
Quinoxaline, Quinoline and 2-Alkylaminoquinoline Derivatives. Chem.
Commun. 2018, 54, 6883−6886. (d) Das, K.; Mondal, A.; Srimani, D.
Phosphine Free Mn-Complex Catalysed Dehydrogenative C−C and
C−heteroatom Bond Formation: A Sustainable Approach to
Synthesize Quinoxaline, Pyrazine, Benzothiazole and Quinoline
Derivatives. Chem. Commun. 2018, 54, 10582−10585. (e) Guo, B.;
Li, H.-X.; Zhang, S.-Q.; Young, D. J.; Lang, J.-P. C-N Bond Formation
Catalyzed by Ruthenium Nanoparticles Supported on N-Doped
Carbon via Acceptorless Dehydrogenation to Secondary Amines,
Imines, Benzimidazoles and Quinoxalines. ChemCatChem 2018, 10,
5627−5636. (f) Chakrabarti, K.; Maji, M.; Kundu, S. Cooperative
Iridium Complex-Catalyzed Synthesis of Quinoxalines, Benzimidazoles
and Quinazolines in Water. Green Chem. 2019, 21, 1999−2004.
(g) Mastalir, M.; Glatz, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K.
Rhenium-Catalyzed Dehydrogenative Coupling of Alcohols and
Amines to Afford Nitrogen-Containing Aromatics and More. Org.
Lett. 2019, 21, 1116−1120.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Founda-
tion of China (grant nos. 21672192, 21803059, and U1904212)
is gratefully appreciated.
REFERENCES
■
(1) (a) Ajani, O. O. Present Status of Quinoxaline Motifs: Excellent
Pathfinders in Therapeutic Medicine. Eur. J. Med. Chem. 2014, 85,
688−715. (b) Pereira, J. A.; Pessoa, A. M.; Cordeiro, M. N. D. S.;
̂
Fernandes, R.; Prudencio, C.; Noronha, J. P.; Vieira, M. Quinoxaline,
Its Derivatives and Applications: A State of the Art Review. Eur. J. Med.
Chem. 2015, 97, 664−672. (c) Kaushal, T.; Srivastava, G.; Sharma, A.;
Negi, A. S. An Insight into Medicinal Chemistry of Anticancer
Quinoxalines. Bioorg. Med. Chem. 2019, 27, 16−35.
(2) Achelle, S.; Baudequin, C.; Ple, N. Luminescent Materials
Incorporating Pyrazine or Quinoxaline Moieties. Dyes Pigm. 2013, 98,
́
575−600.
́
(3) Mathew, T.; Papp, A. A.; Paknia, F.; Fustero, S.; Prakash, G. K. S.
Benzodiazines: Recent Synthetic Advances. Chem. Soc. Rev. 2017, 46,
3060−3094.
(4) (a) More, S. V.; Sastry, M. N. V.; Yao, C.-F. Cerium (iv)
Ammonium Nitrate (CAN) as a Catalyst in Tap Water: A Simple,
Proficient and Green Approach for the Synthesis of Quinoxalines. Green
Chem. 2006, 8, 91−95. (b) Zhang, C.; Xu, Z.; Zhang, L.; Jiao, N. Et3N-
Catalyzed Oxidative Dehydrogenative Coupling of α-Unsubstituted
Aldehydes and Ketones with Aryl Diamines Leading to Quinoxalines
using Molecular Oxygen as Oxidant. Tetrahedron 2012, 68, 5258−
5262. (c) Pandit, R. P.; Kim, S. H.; Lee, Y. R. Iron-Catalyzed
Annulation of 1,2-Diamines and Diazodicarbonyls for Diverse and
Polyfunctionalized Quinoxalines, Pyrazines, and Benzoquinoxalines in
Water. Adv. Synth. Catal. 2016, 358, 3586−3599. (d) Viswanadham, K.
K. D. R.; Reddy, M. P.; Sathyanarayana, P.; Ravi, O.; Kant, R.; Bathula,
S. R. Iodine-mediated Oxidative Annulation for One-Pot Synthesis of
Pyrazines and Quinoxalines using a Multipathway Coupled Domino
Strategy. Chem. Commun. 2014, 50, 13517−13520. (e) Okumura, S.;
Takeda, Y.; Kiyokawa, K.; Minakata, S. Hypervalent Iodine(iii)-
Induced Oxidative [4+2] Annulation of o-Phenylenediamines and
Electron-Deficient Alkynes: Direct Synthesis of Quinoxalines from
Alkyne Substrates under Metal-Free Conditions. Chem. Commun. 2013,
́
49, 9266−9268. (f) Vidal-Albalat, A.; Rodríguez, S.; Gonzalez, F. V.
Nitroepoxides as Versatile Precursors to 1,4-Diamino Heterocycles.
Org. Lett. 2014, 16, 1752−1755. (g) Kumar, K.; Mudshinge, S. R.;
Goyal, S.; Gangar, M.; Nair, V. A. A Catalyst Free, One Pot Approach
for the Synthesis of Quinoxaline Derivatives via Oxidative Cyclisation
of 1,2-diamines and Phenacyl Bromides. Tetrahedron Lett. 2015, 56,
1266−1271. (h) Shen, J.; Wang, X.; Lin, X.; Yang, Z.; Cheng, G.; Cui, X.
One-Pot Regiospecific Synthesis of Quinoxalines via a CH2-Extrusion
Reaction. Org. Lett. 2016, 18, 1378−1381.
(5) (a) Ma, H.; Li, D.; Yu, W. Synthesis of Quinoxaline Derivatives via
Tandem Oxidative Azidation/Cyclization Reaction of N-Arylenamines.
Org. Lett. 2016, 18, 868−871. (b) Yang, Z.-J.; Liu, C.-Z.; Hu, B.-L.;
Deng, C.-L.; Zhang, X.-G. Oxidative Tandem Nitrosation/Cyclization
J
https://dx.doi.org/10.1021/acs.joc.0c02453
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(11) (a) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. Iron Sulfide
Catalyzed Redox/Condensation Cascade Reaction between 2-Amino/
Hydroxy Nitrobenzenes and Activated Methyl Groups: A Straightfor-
ward Atom Economical Approach to 2-Hetaryl-benzimidazoles and
−benzoxazoles. J. Am. Chem. Soc. 2013, 135, 118−121. (b) Nguyen, T.
B.; Ermolenko, L.; Retailleau, P.; Al-Mourabit, A. Elemental Sulfur
Disproportionation in the Redox Condensation Reaction between o-
Halonitrobenzenes and Benzylamines. Angew. Chem., Int. Ed. 2014, 53,
13808−13812. (c) Tang, L.; Guo, X.; Yang, Y.; Zha, Z.; Wang, Z. Gold
Nanoparticles Supported on Titanium Dioxide: an Efficient Catalyst for
Highly Selective Synthesis of Benzoxazoles and Benzimidazoles. Chem.
Commun. 2014, 50, 6145−6148. (d) Xie, F.; Zhang, M.; Chen, M.; Lv,
W.; Jiang, H. Convenient Synthesis of Quinolines from α-2-Nitroaryl
Alcohols and Alcohols via a Ruthenium-catalyzed Hydrogen Transfer
Strategy. ChemCatChem 2015, 7, 349−353. (e) Tang, L.; Yang, Z.; Sun,
T.; Zhang, D.; Ma, X.; Rao, W.; Zhou, Y. Unexpected Decarboxylation-
Triggered o-Hydroxyl-Controlled Redox Condensation of Phenyl-
glycines with 2-Nitrophenols in Aqueous Media. Adv. Synth. Catal.
2018, 360, 3055−3062. (f) Xing, Q.; Ma, Y.; Xie, H.; Xiao, F.; Zhang,
F.; Deng, G.-J. Iron-Promoted Three-Component 2-Substituted
Benzothiazole Formation via Nitroarene ortho-C−H Sulfuration with
Elemental Sulfur. J. Org. Chem. 2019, 84, 1238−1246. (g) Das, S.;
Mallick, S.; De Sarkar, S. Cobalt-Catalyzed Sustainable Synthesis of
Benzimidazoles by Redox-Economical Coupling of o-Nitroanilines and
Alcohols. J. Org. Chem. 2019, 84, 12111−12119.
(12) (a) Nguyen, T. B.; Le Bescont, J.; Ermolenko, L.; Al-Mourabit, A.
Cobalt- and Iron-Catalyzed Redox Condensation of o-Substituted
Nitrobenzenes with Alkylamines: A Step- and Redox-Economical
Synthesis of Diazaheterocycles. Org. Lett. 2013, 15, 6218−6221.
(b) Xie, F.; Zhang, M.; Jiang, H.; Chen, M.; Lv, W.; Zheng, A.; Jian, X.
Efficient Synthesis of Quinoxalines from 2-nitroanilines and Vicinal
Diols via a Ruthenium-Catalyzed Hydrogen Transfer Strategy. Green
Chem. 2015, 17, 279−284. (c) Nguyen, T.; Al-Mourabit, A.;
Ermolenko, L. Sodium Sulfide: A Sustainable Solution for Unbalanced
Redox Condensation Reaction between o-Nitroanilines and Alcohols
Catalyzed by an Iron−Sulfur System. Synthesis 2015, 47, 1741−1748.
(d) Shee, S.; Panja, D.; Kundu, S. Nickel-Catalyzed Direct Synthesis of
Quinoxalines from 2-Nitroanilines and Vicinal Diols: Identifying
Nature of the Active Catalyst. J. Org. Chem. 2020, 85, 2775−2784.
(13) Porcheddu, A.; Chelucci, G. Base-Mediated Transition-Metal-
Free Dehydrative C−C and C−N Bond-Forming Reactions from
Alcohols. Chem. Rec. 2019, 19, 2398−2435.
(14) (a) Xu, Q.; Chen, J.; Tian, H.; Yuan, X.; Li, S.; Zhou, C.; Liu, J.
Catalyst-Free Dehydrative α-Alkylation of Ketones with Alcohols:
Green and Selective Autocatalyzed Synthesis of Alcohols and Ketones.
Angew. Chem., Int. Ed. 2014, 53, 225−229. (b) Liang, Y.-F.; Zhou, X.-F.;
Tang, S.-Y.; Huang, Y.-B.; Feng, Y.-S.; Xu, H.-J. Lithium tert-Butoxide
Mediated α-Alkylation of Ketones with Primary Alcohols under
Transition-Metal-Free Conditions. RSC Adv. 2013, 3, 7739−7742.
(15) Xu, Q.; Chen, J.; Liu, Q. Aldehyde-Catalyzed Transition Metal-
Free Dehydrative β-Alkylation of Methyl Carbinols with Alcohols. Adv.
Synth. Catal. 2013, 355, 697−704.
(16) (a) Li, S.; Li, X.; Li, Q.; Yuan, Q.; Shi, X.; Xu, Q. Structure-
Dependent Tautomerization Induced Catalyst-Free Autocatalyzed N-
alkylation of Heteroaryl Amines with Alcohols. Green Chem. 2015, 17,
3260−3265. (b) Li, Q.-Q.; Xiao, Z.-F.; Yao, C.-Z.; Zheng, H.-X.; Kang,
Y.-B. Direct Alkylation of Amines with Alcohols Catalyzed by Base. Org.
Lett. 2015, 17, 5328−5331. (c) Xiao, M.; Yue, X.; Xu, R.; Tang, W.;
Xue, D.; Li, C.; Lei, M.; Xiao, J.; Wang, C. Transition-Metal-Free
Hydrogen Autotransfer: Diastereoselective N-Alkylation of Amines
with Racemic Alcohols. Angew. Chem., Int. Ed. 2019, 58, 10528−10536.
(d) Pothikumar, R.; Bhat, V. T.; Namitharan, K. Pyridine Mediated
Transition-Metal-Free Direct Alkylation of Anilines Using Alcohols via
Borrowing Hydrogen Conditions. Chem. Commun. 2020, 56, 13607−
13610.
W.; Xiong, B.; Tan, Z.; Jiang, H.; Zhang, M. Straightforward Synthesis
of 2-Arylquinoxalines from 2-Nitroanilines with an Equimolar Amount
of Monoalcohols via a Base-Catalyzed Hydrogen-Transfer Coupling
Reaction. Asian J. Org. Chem. 2015, 4, 1127−1131. (c) Xiong, B.;
Zhang, S.; Jiang, H.; Zhang, M. Hydrogen-Transfer-Mediated Direct β-
Alkylation of Aryl-1,8-naphthyridines with Alcohols under Transition
Metal Catalyst Free Conditions. Org. Lett. 2016, 18, 724−727. (d) Yao,
S.; Zhou, K.; Wang, J.; Cao, H.; Yu, L.; Wu, J.; Qiu, P.; Xu, Q. Synthesis
of 2-Substituted Quinazolines by CsOH-mediated Direct Aerobic
Oxidative Cyclocondensation of 2-Aminoarylmethanols with Nitriles in
Air. Green Chem. 2017, 19, 2945−2951. (e) Wang, Q.; Lv, M.; Liu, J.;
Li, Y.; Xu, Q.; Zhang, X.; Cao, H. Efficient Synthesis of Quinazolinones
by Transition-Metal-Free Direct Aerobic Oxidative Cascade Annula-
tion of Alcohols with o-Aminoarylnitriles. ChemSusChem 2019, 12,
3043−3048. (f) Roy, B. C.; Ansari, I. A.; Samim, S. A.; Kundu, S. Base-
Promoted α-Alkylation of Arylacetonitriles with Alcohols. Chem.
Asian J. 2019, 14, 2215−2219. (g) Liu, T.; Wu, K.; Wang, L.; Yu, Z.
Potassium tert-Butoxide-Promoted Acceptorless Dehydrogenation of
N-Heterocycles. Adv. Synth. Catal. 2019, 361, 3958−3964.
(18) (a) Li, K.; Niu, J.-L.; Yang, M.-Z.; Li, Z.; Wu, L.-Y.; Hao, X.-Q.;
Song, M.-P. New Type of 2,6-Bis(imidazo[1,2-a]pyridin-2-yl)pyridine-
Based Ruthenium Complexes: Active Catalysts for Transfer Hydro-
genation of Ketones. Organometallics 2015, 34, 1170−1176. (b) Yang,
F.-L.; Zhu, X.; Rao, D.-K.; Cao, X.-N.; Li, K.; Xu, Y.; Hao, X.-Q.; Song,
M.-P. Highly Efficient Synthesis of Primary Amides via Aldoximes
Rearrangement in Water Under Air Atmosphere Catalyzed by an Ionic
Ruthenium Pincer Complex. RSC Adv. 2016, 6, 37093−37098.
(c) Yang, F.-L.; Wang, Y.-H.; Ni, Y.-F.; Gao, X.; Song, B.; Zhu, X.;
Hao, X.-Q. An Efficient Homogenized Ruthenium(II) Pincer Complex
for N-Monoalkylation of Amines with Alcohols. Eur. J. Org. Chem.
2017, 2017, 3481−3486. (d) Cao, X.-N.; Wan, X.-M.; Yang, F.-L.; Li,
K.; Hao, X.-Q.; Shao, T.; Zhu, X.; Song, M.-P. NNN Pincer Ru(II)-
Complex-Catalyzed α-Alkylation of Ketones with Alcohols. J. Org.
Chem. 2018, 83, 3657−3668. (e) Wan, X.-M.; Liu, Z.-L.; Liu, W.-Q.;
Cao, X.-N.; Zhu, X.; Zhao, X.-M.; Song, B.; Hao, X.-Q.; Liu, G. NNN
Pincer Ru(II)-Catalyzed Dehydrogenative Coupling of 2-Amino-
arylmethanols with Nitriles for the Construction of Quinazolines.
Tetrahedron 2019, 75, 2697−2705. (f) Zhu, Z.-H.; Li, Y.; Wang, Y.-B.;
Lan, Z.-G.; Zhu, X.; Hao, X.-Q.; Song, M.-P. α-Alkylation of Nitriles
with Alcohols Catalyzed by NNN′ Pincer Ru(II) Complexes Bearing
Bipyridyl Imidazoline Ligands. Organometallics 2019, 38, 2156−2166.
(19) (a) Ben-Harush, K.; Wolfson, A.; Herskowitz, M. Unexpected
Performance of Solid Alkaline Metal Hydroxides in Liquid Phase
Oxidation of 1-Phenylethanol. Lett. Org. Chem. 2006, 3, 664−667.
́
(b) Martínez, R.; Ramon, D. J.; Yus, M. Transition-Metal-Free Indirect
̈
Friedlander Synthesis of Quinolines from Alcohols. J. Org. Chem. 2008,
73, 9778−9780. (c) Zhu, M.; Wang, C.; Tang, W.; Xiao, J. Transition-
Metal-Free Synthesis of Quinolines from 2-Nitrobenzyl Alcohol in
Water. Tetrahedron Lett. 2015, 56, 6758−6761.
(20) (a) Wolfson, A.; Ben-Harush, K.; Herskowitz, M. Aerobic
Oxidation of Benzylic Alcohols with Solid Alkaline Metal Hydroxides.
Kinet. Catal. 2010, 51, 63−68. (b) Ouali, A.; Majoral, J.-P.; Caminade,
A.-M.; Taillefer, M. NaOH-Promoted Hydrogen Transfer: Does
NaOH or Traces of Transition Metals Catalyze the Reaction?
ChemCatChem 2009, 1, 504−509.
(21) Xu, Q.; Li, Q.; Zhu, X.; Chen, J. Green and Scalable Aldehyde-
Catalyzed Transition Metal-Free Dehydrative N-Alkylation of Amides
and Amines with Alcohols. Adv. Synth. Catal. 2013, 355, 73−80.
(22) (a) Ballester, J.; Caminade, A.-M.; Majoral, J.-P.; Taillefer, M.;
Ouali, A. Efficient and Eco-compatible Transition Metal-free
Oppenauer-type Oxidation of Alcohols. Catal. Commun. 2014, 47,
58−62.
(23) Li, X.; Sun, L.; Zhang, Q.; Li, S.; Wang, Y.; Wei, D.; Zhang, W.;
Lan, Y. Mechanism and Substituent Effects of Benzene Arylation via a
Phenyl Cation Strategy: A Density Functional Theory Study.
ChemCatChem 2019, 11, 5068−5076.
(24) Liu, X.; Zhang, Y.-M. A Convenient Method for Pinacolic
Coupling of Aromatic Carbonyl Compounds Promoted by Zinc
(17) (a) Shi, X.; Guo, J.; Liu, J.; Ye, M.; Xu, Q. Unexpectedly Simple
Synthesis of Benzazoles by tBuONa-Catalyzed Direct Aerobic
Oxidative Cyclocondensation of o-Thio/ Hydroxy/ Aminoanilines
with Alcohols under Air. Chem.Eur. J. 2015, 21, 9988−9993. (b) Lv,
K
https://dx.doi.org/10.1021/acs.joc.0c02453
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Powder in Dilute Hydrochloric Acid. Chin. J. Org. Chem. 2003, 23, 92−
94.
(25) Zeynizadeh, B.; Behyar, T. Wet THF as Suitable Solvent for a
Mild and convenient Reduction of Carbonyl Compounds with NaBH4.
Bull. Chem. Soc. Jpn. 2005, 78, 307−315.
(26) Patil, B. N.; Lade, J. J.; Parab, A. A.; Sathe, P. A.; Vadagaonkar, K.
S.; Chaskar, A. C. NBS-assisted an Efficient Conversion of Styrenes to
-hydroxy Ketones in Water. Tetrahedron Lett. 2019, 60, 1788−1791.
L
https://dx.doi.org/10.1021/acs.joc.0c02453
J. Org. Chem. XXXX, XXX, XXX−XXX